Association between various cathepsins and uterine leiomyoma: A Mendelian randomization analysis

Tingxiu Liu, Yuehan Ren, Junning Zhang, Hechun Yin, Zheng Zheng, Mingyue Zhang, Liao Yan, Liangliang Yang, Chang Liu, X. Liu, Xinmin Liu, Peiyu Yan
In: PLOS ONE · 2024 · vol. 19(9) , pp. e0310292 · doi:10.1371/journal.pone.0310292 · PMID:39264885 · W4402476232
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

This Mendelian randomization analysis found that cathepsin B is associated with an increased risk of uterine leiomyoma, although this association did not persist after further statistical adjustments.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-09 ⓘ

This study used a bidirectional two-sample Mendelian randomization approach in European-ancestry datasets to test whether genetic proxies for nine cathepsins (including CTSB) causally influence risk of uterine leiomyoma, and vice versa. Using instrumental variables from GWAS summary statistics and sensitivity analyses (MR-Egger intercept, MR-PRESSO, heterogeneity tests, and leave-one-out), the authors found an association between higher cathepsin B (CTSB) and increased uterine leiomyoma risk in analyses that excluded cancers (OR ≈ 1.06, P≈0.009), while many other cathepsins showed no effects. However, the CTSB effect did not persist after certain filters such as multiple testing or Steiger filtering, and after removing specific SNPs the statistical difference disappeared, suggesting limited robustness. This paper does not explicitly discuss adenomyosis, but it is directly relevant to endometriosis research through its investigation of a molecular pathway (cathepsin B) that is also implicated in inflammatory and protease-driven processes often studied in endometriosis, and it is centrally about endometriosis-related mechanisms only insofar as it studies endometriosis-adjacent protease biology rather than endometriosis itself.

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Abstract

Emerging evidence suggests a tentative association between cathepsins and uterine leiomyoma (UL). Previous investigations have predominantly focused on the role of cathepsins in the metastasis and colonization of gynecological malignancies. Still, observational studies may lead to confounding and biases. We employed a bidirectional Mendelian randomization (MR) analysis to elucidate the causative links between various cathepsins and UL. Instrumental variables (IVs) of cathepsins and UL within the European cohort were from extant genome-wide association study datasets. Sensitivity assessments was executed, and the heterogeneity of the findings was meticulously dissected to affirm the solidity of the outcomes. Our findings reveal the association between cathepsin B (CTSB) and an elevated risk of developing UL (all cancers excluded) [Inverse Variance Weighted (IVW) method]: OR = 1.06, 95%CI [1.02, 1.11], P = 0.008895711. Although the association does not persist after multiple testing or Steiger filtering, this finding adds to our understanding of the causal relationship between CTSB of various cathepsins and UL (all cancers excluded) and may herald new therapeutic avenues for individuals affected by this condition.

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